MR Dictionary

Mendelian randomization (MR)

Synonyms: Mendelian randomisation (MR)

A method that uses genetic variants (usually single nucleotide polymorphisms (SNPs)) as instrumental variables (IVs) to explore causal effects of exposures on outcomes in observational epidemiological studies.

Genetic IVs must fulfil the MR assumptions (as defined by IV analyses). In most MR studies, the assumption that is most likely to be violated is the exclusion restriction assumption due to horizontal pleiotropy. See IV.

MR framework. (A) MR relies on the following three core assumptions: (1) the genetic variant(s) being used as an instrument (Z) is associated with the exposure (X) (often referred to as the relevance assumption); (2) there are no measured and unmeasured confounders of the instrument (Z) and the outcome (Y) (often referred to as the independence assumption); and (3) there is no independent pathway between the instrument (Z) and outcome (Y) other than through the exposure (X) (often referred to as the exclusion restriction or no horizontal pleiotropy assumption). (B) MR can be perceived as being analogous to a randomized controlled trial (RCT), whereby the random assortment of alleles at conception is equivalent to the randomization method with an RCT. This randomization process produces groups of individuals who differ with respect to the intervention (i.e., genetic variation in the case of MR) and between which confounders are equally distributed. Therefore, any differences observed in the outcome of interest between these randomly allocated groups should be due to the exposure with which the genetic variant(s) are associated. (C) Whilst, traditionally, the MR assumptions are usually depicted as in (A), this is a simplification of the three core assumptions and may be misleading. Consider the arrow linking the instrument (Z) and confounders of the exposure-outcome association (U) as depicted in (A). The random inheritance of alleles at conception provides genotypic groups at a population level between which confounders of the exposure-outcome association should be equally distributed. Coupled with the fact that confounders of the exposure-outcome association are unlikely to affect genetic variation, the arrow in this specific diagram realistically cannot go from U to Z (as depicted) but would, instead, pass from Z to U. However, this provides no distinction between the second and third MR assumptions, as described in (A). Instead, the second MR assumption refers to population-level confounders that could distort the relationship between the instrument and outcome, including intergenerational (e.g., dynastic ) effects, assortative mating or population structure or stratification. Therefore, to avoid this confusion, the three core MR assumptions are beginning to be depicted separately as in (C), where the first, second and third MR assumptions are depicted on the left, middle and right, respectively. Here, U1 represents confounders of the exposure-outcome association and U2 represents confounders of the instrument-outcome association, which are likely to be different from U1.
Figure 2.4 - MR framework. (A) MR relies on the following three core assumptions: (1) the genetic variant(s) being used as an instrument (Z) is associated with the exposure (X) (often referred to as the relevance assumption); (2) there are no measured and unmeasured confounders of the instrument (Z) and the outcome (Y) (often referred to as the independence assumption); and (3) there is no independent pathway between the instrument (Z) and outcome (Y) other than through the exposure (X) (often referred to as the exclusion restriction or no horizontal pleiotropy assumption). (B) MR can be perceived as being analogous to a randomized controlled trial (RCT), whereby the random assortment of alleles at conception is equivalent to the randomization method with an RCT. This randomization process produces groups of individuals who differ with respect to the intervention (i.e., genetic variation in the case of MR) and between which confounders are equally distributed. Therefore, any differences observed in the outcome of interest between these randomly allocated groups should be due to the exposure with which the genetic variant(s) are associated. (C) Whilst, traditionally, the MR assumptions are usually depicted as in (A), this is a simplification of the three core assumptions and may be misleading. Consider the arrow linking the instrument (Z) and confounders of the exposure-outcome association (U) as depicted in (A). The random inheritance of alleles at conception provides genotypic groups at a population level between which confounders of the exposure-outcome association should be equally distributed. Coupled with the fact that confounders of the exposure-outcome association are unlikely to affect genetic variation, the arrow in this specific diagram realistically cannot go from U to Z (as depicted) but would, instead, pass from Z to U. However, this provides no distinction between the second and third MR assumptions, as described in (A). Instead, the second MR assumption refers to population-level confounders that could distort the relationship between the instrument and outcome, including intergenerational (e.g., dynastic ) effects, assortative mating or population structure or stratification. Therefore, to avoid this confusion, the three core MR assumptions are beginning to be depicted separately as in (C), where the first, second and third MR assumptions are depicted on the left, middle and right, respectively. Here, U1 represents confounders of the exposure-outcome association and U2 represents confounders of the instrument-outcome association, which are likely to be different from U1.

References

Other terms in 'Definition of MR and study designs':